Late pregnancy progesterone treatment as a modulatory signal for postpartum behavior.

Changes in plasma progesterone levels during late pregnancy are a determining factor in the expression of maternal behavior during lactation. Previous studies showed that mild opioidergic stimulation during late pregnancy makes lactating females more sensitive to opioidergic-induced inhibition of maternal behavior and more willing to display hunting behavior. Such previous behaviorally meaningful opioidergic stimulation also selectively increased serum progesterone levels. The present study tested whether progesterone treatment during late pregnancy interferes with the display of maternal behavior and behavioral selection during lactation. In Experiment 1, rats were treated with progesterone (400 and 500 µg per day) from the 17th day to the 22nd day of pregnancy. The lowest progesterone dose did not interfere with pregnancy or parturition, and this dose was used in Experiments 2 and 3, in which the rats were treated with subcutaneous progesterone or peanut oil for 5 days beginning on pregnancy day 17. On day 5 of lactation, dams were challenged with subcutaneous morphine (1.5 mg/kg), or saline. The rats were then tested for maternal care (Experiment 2) or behavioral selection with pups and cockroaches (Experiment 3). Animals treated with progesterone during late pregnancy and challenged with morphine during lactation exhibited a significant decrease in maternal behavior in both Experiments 2 and 3. Predatory hunting was not modified by progesterone treatment. These results indicate that sensitivity to opioidergic-mediated inhibition of maternal behavior is enhanced by prepartum progesterone administration. Thus progesterone might be part of the opioid-triggered prepartum signaling leading to behavioral changes during lactation.

Morphine-induced changes in opioid sensitivity in postpartum females: a unique progesterone response.

Opioid peptides play an important role in maternal behaviour, as well as in physiological and pathological phenomena involving motivation. Daily 3.5 mg/kg doses of morphine from days 17-21 of pregnancy are able to change the expression of maternal behaviour patterns. However, the role of hormones on such opioid behavioural actions remains to be determined. The present study investigated the endocrine responses to this morphine treatment. Corticosterone, progesterone, oestradiol and prolactin serum concentrations were measured after each morphine injection. No significant differences were found in corticosterone, oestradiol or prolactin serum concentrations. The results suggest that the treatment was unable to promote different effects, other than those caused by saline injections. In morphine-treated animals, however, progesterone concentrations were consistently and significantly increased from days 18-20 of treatment. Thus, because this behavioural meaningful opioidergic stimulation during late pregnancy affects progesterone levels, the findings of the present study raise the hypothesis that this hormone may play a role in morphine-induced changes in opioid sensitivity during late pregnancy and early lactation.

Morphine infusions into the rostrolateral periaqueductal gray affect maternal behaviors

It is well established that morphine inhibits maternal behaviors. Previous studies by our group have shown activation of the rostrolateral periaqueductal gray (rlPAG) upon inhibition-intended subcutaneous injections of morphine. In this context, we demonstrated that a single naloxone infusion into the rlPAG, following this opioid-induced inhibition, reactivated maternal behaviors. Since these data were obtained by using peripheral morphine injections, the present study was designed to test whether morphine injected directly into the rlPAG would affect maternal behaviors. Our hypothesis that morphine acting through the rlPAG would disrupt maternal behaviors was confirmed with a local infusion of morphine. The mothers showed shorter latency for locomotor behavior to explore the home cage (P = 0.049). Inhibition was especially evident regarding retrieving (P = 0.002), nest building (P = 0.05) and full maternal behavior (P = 0.023). These results support the view that opioidergic transmission plays a behaviorally meaningful inhibitory role in the rostrolateral PAG.

Morphine infusions into the rostrolateral periaqueductal gray affect maternal behaviors.

It is well established that morphine inhibits maternal behaviors. Previous studies by our group have shown activation of the rostrolateral periaqueductal gray (rlPAG) upon inhibition-intended subcutaneous injections of morphine. In this context, we demonstrated that a single naloxone infusion into the rlPAG, following this opioid-induced inhibition, reactivated maternal behaviors. Since these data were obtained by using peripheral morphine injections, the present study was designed to test whether morphine injected directly into the rlPAG would affect maternal behaviors. Our hypothesis that morphine acting through the rlPAG would disrupt maternal behaviors was confirmed with a local infusion of morphine. The mothers showed shorter latency for locomotor behavior to explore the home cage (P = 0.049). Inhibition was especially evident regarding retrieving (P = 0.002), nest building (P = 0.05) and full maternal behavior (P = 0.023). These results support the view that opioidergic transmission plays a behaviorally meaningful inhibitory role in the rostrolateral PAG.

Preliminary study of the effects of morphine treatment on opioid receptor gene expression in brain structures of the female rat.

Opioid receptors play an important role in female physiology. They modulate directly and indirectly neuroendocrine phenomena that influence pregnancy maintenance, pain threshold, parturition, lactation, maternal behavior, rewarding and addiction. Thus understanding the gene expression levels of the three major opioid receptors, mu, delta and kappa in different brain regions is essential for investigating dynamic mechanisms of opioidergic transmission. Adult virgin female rats were treated acutely with morphine sulfate (3.5 mg/kg or 20 mg/kg s.c.) or chronically for 5 days (3.5 mg/kg). Rats were killed 1 h after the last injection. In the acute treatment, expression levels for the encoded mu-opioid receptor Oprm1, as detected by reverse transcription-polymerase chain reaction, were significantly decreased in the periaqueductal gray. In chronic treatment, both Oprk1 and Oprm1 expression levels, that encoded kappa and mu-opioid receptor respectively, showed significant decreases in the periaqueductal gray and striatum. Regional changes in opioid receptor gene expression levels might reflect highly specialized roles for these receptors with possible functional meaning for the plasticity of the opioidergic transmission.

A role for the periaqueductal gray in switching adaptive behavioral responses.

Previous studies suggested a role for the rostral lateral periaqueductal gray (PAG) in the inhibition of maternal behavior induced by low doses of morphine in dams with previous morphine experience. In the present study, we first showed that unilateral NMDA lesions placed in this particular PAG region prevented the morphine-induced inhibition of maternal behavior in previously morphine-sensitized dams. As suggested by previous Fos data on the PAG, predatory hunting appears as a likely candidate to replace maternal behavior in the morphine-treated dams. By testing saline- and morphine-treated dams with live cockroaches only, we have presently shown that morphine challenge increased insect hunting. Moreover, morphine- and saline-treated dams were also observed in an environment containing pups and roaches. Although most of the saline-treated animals displayed active nursing and only occasionally presented insect hunting, all of the morphine-treated animals ignored the pups and avidly pursued and caught the roaches. We next questioned whether the rostral lateral PAG would be involved in this behavioral switch. Our results showed that unilateral lesions of the rostral lateral PAG, but not other parts of the PAG, partially impaired predatory hunting and restored part of the maternal response. Moreover, bilateral lesions of the rostral lateral PAG produced even more dramatic effects in inhibiting insect hunting and restoring maternal behavior. The present findings indisputably show that the rostral lateral PAG influences switching from maternal to hunting behavior in morphine-treated dams, thus supporting a previously unsuspected role for the PAG in selecting adaptive behavioral responses.